This invention relates to a method for preparing 4-substituted-4-cyanocyclohexancarboxylic acids. Exemplary compounds are useful as PDE 4 inhibitors.
The process of this invention relates to making compounds which are useful in treating diseases modulated by the isoforms of the phosphodiesterase 4 enzyme. The novel intermediates and processes of this invention are useful in making acids which are known PDE 4 inhibitors. They are useful for, among other things, treating pulmonary diseases such as chronic obstructive pulmonary disease (COPD) and asthma. The compounds which are prepared by the methods of this invention are described in, for example U.S. Pat. No. 5,554,238 issued 03 Sep., 1996. That patent is incorporated here by reference in full. Those compounds, particularly the 4-cyanocyclohexanoic acids, have marked effects on neutrophil activity, inhibiting neutrophil chemotaxis and degranulation in vitro. In animal models, those compounds reduce neutrophil extravasation from the circulation, pulmonary sequestration and the edematous responses to a number inflammatory insults in vivo. They have been found to be useful in treating COPD in humans, and possibly in other mammalian species which suffer from COPD.
In a first aspect, this invention relates to a process for preparing a compound of formula (I) 
where
R is halo, C1-6alkyl, C1-6alkyl substituted with 1 to 4 halogens, C1-6alkoxy, C1-6alkenyl, xe2x80x94Oxe2x80x94(CH2)mcycloalkyl of 3-6 carbons;
n is 1-5;
m is 0-6; and
Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or CO(O)X where X is hydrogen or C1-6alkyl;
which process comprises decarboxylating the diester or diacid of Formula (A) 
where R1 is hydrogen or a C1-6alkyl-ester forming group and R and n are the same as for Formula (I).
In a further aspect this invention relates to a compound of formula (A) per se.
In a third aspect this invention relates to preparing certain other intermediates that are useful in preparing the diester or di-acid of Formula (A), and the intermediates themselves, i.e:
a compound of Formula (B) 
wherein R and n are the same as in Formula (I) and M is OH, an activated hydroxyl group, or halo; and
a compound of Formula (C) 
wherein R and n are the same as in Formula (I).
In yet another aspect, the invention provides a method for making a compound of Formula (C) by treating the nitrile of formula (D) 
where R and n are the same as defined above, with 2-chloroethyl vinyl ether and a strong base.
This invention also provides a method for preparing a compound of Formula (I) which comprises
a. converting the vinylethyl ether of Formula (C) 
wherein R and n are halo, C1-6alkyl, C1-6alkyl substituted with 1 to 4 halogens, C1-6alkoxy, C1-6alkenyl, xe2x80x94Oxe2x80x94(CH2)mcycloalkyl of 3-6 carbons;
n is 1-5;
m is 0-6;
to a compound of Formula (B) 
where M is OH,
b. converting the hydroxyl group of Formula (B) to a compound of Formula (B) where M is a tosylate, mesylate or a triflate,
c. converting the tosylate, mesylate or triflate in Formula (B) to a compound of Formula (B) where M is halo,
d. treating the di-halo compound with dialkyl malonate to obtain a compound of Formula (A) 
where R1 is lower alkyl,
e. optionally saponfying the diester of Formula (A) to obtain a compound of Formula (A) where R1 is hydrogen; and
f. decarboxylating a compound of Formula (A) where R1 is hydrogen or C1-6alkyl to obtain a compound for Formula (I) where one of Rxe2x80x2 is hydrogen and the other is CO(O)X where X is C1-6alkyl or hydrogen.
This invention provides a method for preparing cyclohexanoic acids. In particular it provides an alternative means for preparing the cyclohexanoic acids disclosed in U.S. Pat. No. 5,554,238 where the 4-position on the cyclohexane ring has a CN group.
xe2x80x9cHaloxe2x80x9d as used herein includes fluoro, chloro, bromo, and iodo. xe2x80x9cHalidexe2x80x9d includes fluoride, chloride, bromide and iodide.
For all of the compounds disclosed herein, a preferred embodiment is one where there are two R groups, i.e. n is 2. Most preferred are those compounds where one R group is at the 3 position and the second R group is on the 4 position of the benzene ring. More particularly it is preferred that each R group be independently C4-6cycloalkyloxy or C1-2alkoxy unsubstituted or substituted by 1 or more halogens. More preferred are methoxy, C1-2alkoxy substituted by up to 3 fluoro atoms, cyclopropylmethoxy or cyclopentyloxy. The more preferred R groups are those wherein the 4-position R group is methoxy, xe2x80x94Oxe2x80x94CF3, xe2x80x94Oxe2x80x94CHF2, or xe2x80x94Oxe2x80x94CH2CHF2, and the 3-position R group is cyclopropylmethoxy or cyclopentyloxy.
In Formula (A) the most preferred R1 groups are hydrogen, methyl or ethyl.
In Formula (B) the most preferred M groups are OH, tosyl and iodo.
The most preferred product of the process of this invention are those compounds which have a 3-cyclopentyloxy-4-methoxyphenyl substitution pattern.
Reaction Scheme I provides a diagrammatic overview of the intermediates and chemistries employed in this invention. 
The starting material 3-cyclopentyloxy-4-methoxybenzeneacetonitrile is a known compound. See for example U.S. Pat. No. 5,449,686. The 2-chloroethylvinyl ether is commercially available (Aldrich). To effect the reaction, a strong base is charged to a reaction vessel containing a suitable non-polar solvent to which the vinyl ether is added. This mixture is heated to between about 30 to 70xc2x0 C. and charged with the benzeneacetonitrile (A) pre-dissolved in the same solvent as the base and the vinyl ether. Toluene is a preferred solvent. A preferred base is sodium amide. The amount of base is equivalent, on a molar basis, to that of the vinyl ether. Both are used in about a three-fold excess relative to the substrate. After the benzeneacetonitrile has been charged to the reaction flask, the solution is further heated to around 80xc2x0 C. more or less. Usually the reaction is complete in about 30 minutes to 2 hours. The product (1-1) is isolated using standard procedures.
The bis 2-hydroxyethyl compound (1-2)is prepared by treating the vinyl ether moiety prepared as per the preceding paragraph with a strong mineral acid in an aqueous solvent. For example water can be added to the 2-(ethenyloxy)ethyl compound (1-1), heating that combination to about 70-90xc2x0 C. and then adding a molar excess of a mineral acid such as HCl or the like. A preferred set of conditions is one where the 2-(ethenyloxy)ethyl is treated with water and heated to about 80xc2x0 C. more or less followed by the addition of a 50% molar excess of concentrated HCl. Under these conditions the reaction is complete in 5-20 minutes.
To obtain the halogenated compound 1-4, the diol is converted to a group which can be displaced by a halide ion. For example the diol can be converted to a tosylate, mesylate, or the like, by treating the diol with reagents and under conditions which form the tosylate, etc. By way of example the diol is dissolved in an organic solvent and treated with an excess of p-toluenesulfonyl chloride at room temperature for 3-7 hours. Preferably the reaction is run in pyridine with about a 2.5 molar excess of the p-toluenesulfonyl chloride.
This tosylate (or mesylate, triflate, etc) (1-3) is converted to the di-halo 1-4 by dissolving it in a polar aprotic solvent, and adding a weak base and a halide salt. This mixture is heated to reflux for a number of hours, for example overnight. A preferred solvent is acetone or dimethyl formamide. A preferred halide salt is sodium or lithium iodide though other sodium or potassium salts of fluorine, chlorine and bromine can be used as well. A 2 to 6-fold excess of the halide salt is preferred. Refluxing overnight usually effects completion of the reaction.
Forming the cyclohexane dicarboxylates or diacids 1-5 and 1-6 is effected by charging the di-halo compound (1-4) to a solution of a dialkyl malonate or malonic acid and a weak base in a dipolar aprotic solvent. This slurry is stirred for an extended period of time at an elevated temperature, for example overnight. More specifically sodium or potassium carbonate is combined with the likes of dimethyl malonate in a solvent such as dimethylformamide. Then the di-halo 1-4 is added and the resulting slurry is stirred overnight at about 75-95xc2x0 C. or so. The malonate is added in about a 1:1 molar ratio to that of the di-halo compound.
The diester may be saponified to give the diacid, though this step is not illustrated in Scheme I. This is accomplished by treating the diester with an aqueous base in a water-miscible solvent. For example the diester is charged to a reaction vessel containing the likes of tetrahydrofuran to which is added water and an alkali hydroxide base such as lithium hydroxide. This solution is heated at reflux for a number of hours, for example overnight.
Decarboxylating the diester or dicaid to get the mono-ester or mono-acid is accomplished by dissolving the diester in the likes of dimethylsulfoxide, adding about an equivalent of a base such as pyridine, about 3 equivalents of water and about 3 equivalents of a salt such as lithium chloride. This solution is stirred for several hours at 100 to 150xc2x0 C. or thereabouts for 4-8 hours. Product is extracted from an acidified aqueous solution and further purified by conventional means. The product is a mixture of cis and trans isomers in about a 1:1 ratio. The cis form of the ester or acid can be enriched by dissolving a mixture of isomers in a lower alkanol and treating that solution with the alkali metal salt of the alkanol. A preferred alkanol is t-butanol and a preferred alkali metal salt is potassium t-butanol. The acid may be obtained by saponifying the ester using a base and then acidifying the resulting salt with using a mineral acid, for example.